Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorder thought to result from dysregulation of intestinal motor, sensory and CNS function. In the United States, the estimated prevalence is 15% to 20%, and 75% of patients are women. Despite its prevalence, IBS is poorly understood. It is one of over 20 functional gastrointestinal (GI) disorders that are not explained by identifiable structural or biochemical abnormalities. IBS is characterized by persistent or recurrent symptoms of abdominal pain with diarrhea and/or constipation. IBS is believed to relate to abnormalities in motility and/or afferent sensitivity as mediated by the central nervous system. Patients with IBS have a diminished quality of life and use significant health care resources.
Treatment for patients diagnosed with IBS has included antidepressant drugs, tranquilizers and laxatives. Pharmacological intervention in diarrhea-predominant IBS focuses on the reduction of bowel motility, spasms and transit times. Peripherally acting opiod ligands such as the petidine congeners diphenoxylate and loperamide and the k-opiod agonist fedotozine slow gastrointestinal transit by their effects on the circular and longitudinal muscle. While these drugs show some effects on intestinal motility, their effects on IBS-related abdominal pain and intestinal relief is generally insufficient.
Alosetron, a selective 5-HT3 receptor antagonist closely related to ondansetron in terms of chemistry and pharmacology, is the first compound of this type to be developed for irritable bowel syndrome. Alosetron and its uses are described in, for example, U.S. Pat. No. 6,284,770, which is incorporated herein by reference. A number of different 5-HT3 receptor antagonists have been disclosed, for example those of group A: indisetron, Ro-93777, YM-114, granisetron, talipexole, azasetron, tropisetron, mirtazapine, ramosetron, ondansetron, lerisetron, alosetron, N-3389, zacopride, cilansetron, E-3620, lintopride, KAE-393, itasetron, mosapride and dolasetron.
In UK Patent No. 2209335 there is disclosed, inter alia, the compound 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol4-yl)methyl]-1H-pyrido [4,3-b]indol-1-one, now known as alosetron, and pharmaceutically acceptable salts, solvates and pharmaceutically acceptable equivalents thereof, in particular its hydrochloride salt.
5-HT3 receptor antagonists are known to be useful in the treatment of a variety of conditions involving 5-HT3 receptor-mediated mechanisms, including in particular emesis.
Ondansetron inhibits emesis by blocking 5-HT3 receptors on vagal afferent nerve terminals in the gastrointestinal mucosa and on terminals on the same vagal nerves in the vomiting system located in the dorsal medulla of brain stem. Alosetron, in various animal models, can reduce the increase in intestinal fluid secretion and motility triggered by serotonin release. Alosetron increases sensory threshold to balloon distension of the rectum, either by a direct effect on afferent pain perception, or via an increase in rectal compliance. In addition, 5-HT3 receptor antagonists have been shown to slow colonic transit in man (ondansetron and alosetron). Clinical data for up to 3 months of treatment indicate that alosetron was orally bioavailable and significantly superior to both placebo and the smooth muscle relaxant, mebeverine, in improving perception of visceral pain, spasms and diarrhea in female diarrhea-predominant IBS.
Alosetron received FDA approval for the treatment of IBS in women with diarrhea in early 2000. It is the first drug to have proven efficacy for IBS. Alosetron (Lotronex(trademark)) was launched in the US, its first market and was also launched in Puerto Rico for the treatment of women with irritable bowel syndrome who have diarrhea as the predominant symptom. However, in November 2000, Glaxo Wellcome withdrew alosetron from the US market, prompted by reports of alosetron-associated ischaemic colitis (n=49; characterized by abdominal cramping and pain) and severe constipation (n=21). The FDA also received 3 reports of deaths which were associated with alosetron.
Alosetron has approximately 60% oral bioavailability and a half-life of 1.5 hours. Greater variability was seen in the pharmacokinetic profile in all parameters in females compared with males. Females also had 60% greater drug exposure than males, with mean peak plasma concentration 45-100% higher. This is attributed to lower clearance and volume of distribution in female population. Similar gender-specific differences have been reported for ondansetron. At least 12 metabolites were detected in urine, which were eliminated from plasma with half-lives of approximately 3 hours. 6-Hydroxy-alosetron, which is twice as potent as alosetron was not detected in plasma, however the limit of detection was 6-fold higher than the Ki for this metabolite.
The pattern of fecal and urinary elimination of alosetron and its metabolites is suggestive of enterohepatic recirculation of 6-OH-alosetron, resulting in xe2x80x9cprolongedxe2x80x9d low level exposure. In addition, 6-OH-alosetron glucuronide and a hydroxymethyl metabolite also have potent 5-HT3 receptor binding affinity. The pharmacoynamic effects of these metabolites are unknown. Clearance was predominantly by metabolism and renal excretion. Mass balance studies with radiolabeled drug indicate that the concentration of circulating metabolite is at least 10 fold greater than that of alosetron, yet, two-thirds of the circulating radioactivity cannot be attributed to alosetron or its metabolites. This is due to slower elimination and smaller Vd of the metabolites.
Over 1200 patients with IBS received alosetron for at least 12 weeks during the Phase II and III clinical trials. Constipation was the most commonly reported adverse event, occurring in 28% of those taking alosetron and in 3% of those on placebo. This side effect appears to be dose dependent and constipation occurred more frequently in female patients. This gender difference is perhaps related to the increased drug exposure level in the female patients.
Thus, it would be particularly desirable to find potent and selective 5-HT3 antagonists having comparable pharmacodynamic effect to that of alosetron, with more predictable metabolism and an improved safety profile.
The subject invention provides useful and novel 5-HT3 antagonists and methods of use. The subject invention also provides methods for synthesizing the compounds of the subject invention. In a specific embodiment, the subject invention also provides methods for the treatment of irritable bowel syndrome.
Advantageously, the subject invention provides compounds which are readily metabolized by the physiological metabolic drug detoxification systems. Specifically, in a preferred embodiment, the therapeutic compounds of the subject invention contain an ester group, which does not detract from the ability of these compounds to provide a therapeutic benefit, but which makes these compounds more susceptible to degradation by hydrolases, particularly serum and/or cytosolic esterases. The subject invention further provides methods of treatment comprising the administration of these compounds to individuals in need of 5-HT3 antagonist treatment.